Conditional depletion of Fus in oligodendrocytes leads to motor hyperactivity and increased myelin deposition associated with Akt and cholesterol activation.
Conditional depletion of Fus in oligodendrocytes leads to motor hyperactivity and increased myelin deposition associated with Akt and cholesterol activation.
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作者：
Guzman KM;Brink LE;Rodriguez-Bey G;Bodnar RJ;Kuang L;Xing B;Sullivan M;Park HJ;Koppes E;Zhu H;Padiath Q;Cambi F
FUS（融合在肉瘤中）是一种主要的核多功能RNA/DNA结合蛋白，调节基因表达的多个方面。FUS突变与人类的家族性肌萎缩侧索硬化症（fALS）和额颞叶变性（FTLD）相关。在分子水平上，突变的FUS蛋白在细胞核中减少，但在细胞质颗粒中积累。携带临床相关FUS突变的少突胶质细胞（OL）导致非细胞自主运动神经元疾病进展，这与OL介导的疾病的外在机制一致。全面或在神经元中敲除FUS会导致与FTLD中存在的行为异常相似的行为异常。在这项研究中，我们试图调查是否是一个外在的机制介导的FUS功能的损失，在OL有助于行为表型。我们已经产生了一种新的条件性敲除（cKO），其中Fus选择性耗尽OL（FusOL cKO）。FusOL cKO小鼠表现出增加的新奇感诱导的运动活动和增强的探索行为，这让人联想到FTLD的一些表现。这些表型与髓鞘厚度更大、有髓小直径轴突数量更多相关，而成熟OL数量没有增加。胆固醇生物合成的限速酶（HMGCR）的表达在FusOLcKO的白色物质束中增加，并导致更高的胆固醇含量。此外，在FusOLcKO中，髓鞘形成的重要调节因子Akt的磷酸化增加。总的来说，这项工作揭示了少突胶质细胞Fus通过激活Akt和胆固醇生物合成调节髓鞘沉积的新作用。
FUS (Fused in sarcoma) is a predominantly nuclear multifunctional RNA/DNA binding protein that regulates multiple aspects of gene expression. FUS mutations are associated with familial Amyotrophic Lateral Sclerosis (fALS) and frontotemporal lobe degeneration (FTLD) in humans. At the molecular level, the mutated FUS protein is reduced in the nucleus but accumulates in cytoplasmic granules. Oligodendrocytes (OL) carrying clinically relevant FUS mutations contribute to non-cell autonomous motor neuron disease progression, consistent with an extrinsic mechanism of disease mediated by OL. Knocking out FUS globally or in neurons lead to behavioral abnormalities that are similar to those present in FTLD. In this study, we sought to investigate whether an extrinsic mechanism mediated by loss of FUS function in OL contributes to the behavioral phenotype. We have generated a novel conditional knockout (cKO) in which Fus is selectively depleted in OL (FusOL cKO). The FusOL cKO mice show increased novelty-induced motor activity and enhanced exploratory behavior, which are reminiscent of some manifestations of FTLD. The phenotypes are associated with greater myelin thickness, higher number of myelinated small diameter axons without an increase in the number of mature OL. The expression of the rate-limiting enzyme of cholesterol biosynthesis (HMGCR) is increased in white matter tracts of the FusOLcKO and results in higher cholesterol content. In addition, phosphorylation of Akt, an important regulator of myelination is increased in the FusOLcKO. Collectively, this work has uncovered a novel role of oligodendrocytic Fus in regulating myelin deposition through activation of Akt and cholesterol biosynthesis.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
4.5
作者：
Kang X;Li W;Zhou Y;Ni M
通讯作者：
Ni M
影响因子：
3.5
作者：
Curiel, Julian;Bey, Guillermo Rodriguez;Vanderver, Adeline
通讯作者：
Vanderver, Adeline
影响因子：
3
作者：
Hoessli, DC;Ilangumaran, S;Din, NU
通讯作者：
Din, NU
影响因子：
25
作者：
Kang, Shin H.;Li, Ying;Fukaya, Masahiro;Lorenzini, Ileana;Cleveland, Don W.;Ostrow, Lyle W.;Rothstein, Jeffrey D.;Bergles, Dwight E.
通讯作者：
Bergles, Dwight E.